Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 386
Filtrar
1.
BMC Med ; 19(1): 316, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34856983

RESUMO

BACKGROUND: Although randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed. We evaluated the association between regular use of PPIs and incident stroke and identified population groups at high net risk. METHODS: This is a prospective analysis of 492,479 participants free of stroke from the UK biobank. Incident stroke was identified through linkage to hospital admission and death registries using the International Classification of Diseases (ICD)-10 codes (I60, I61, I63, and I64). We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, prevalent comorbidities, concomitant use of medications, and indications of PPIs. We assessed the risk differences (RDs) according to the baseline Framingham Stroke Risk Score. In the meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (from 1988 to 1 June 2020) for randomized trials comparing PPIs with other interventions, placebo, or no treatment on stroke risk. Results were combined using a fix-effect meta-analysis (Mantel-Haenszel method). RESULTS: We documented 5182 incident strokes over 3,935,030 person-years of follow-up. Regular PPI users had a 16% higher risk of stroke than non-users (HR 1.16, 95% CI 1.06 to 1.27). The estimated effect was similar to our meta-analysis of nine RCTs (case/participants 371/26,642; RR 1.22, 95% CI 1.00 to 1.50; quality of evidence: moderate). The absolute effect of PPI use on stroke increased with the baseline Framingham Stroke Risk Score, with an RD of 1.34‰, 3.32‰, 4.83‰, and 6.28‰ over 5 years for the lowest, quartile 2, quartile 3, and the highest quartile, respectively. CONCLUSIONS: Regular use of PPIs was associated with an increased risk of stroke, with a higher absolute risk observed in individuals with high baseline stroke risk. Physicians should therefore exercise caution when prescribing PPIs. An assessment of the underlying stoke risk is recommended for individualized use of PPIs.

2.
Front Immunol ; 12: 691713, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925310

RESUMO

Objective: To investigate the characteristics of the tumor immune microenvironment in patients with gastrointestinal stromal tumor (GIST) and identify cancer stem-like properties of GIST to screen potential druggable molecular targets. Methods: The gene expression data of 60 patients with GIST was retrieved from the Array Express database. CIBERSORT was applied to calculate the level of immune infiltration. ssGSEA and ESTIMATE were used to calculate the cancer stemness index and tissue purity. The Connectivity Map (CMAP) database was implemented to screen targeted drugs based on cancer stem-like properties of GIST. Result: There was a difference in the level of immune infiltration between the metastasis and non-metastasis GIST groups. The low level of T-cell infiltration was correlated with high tumor purity and tumor stemness index, and the correlation coefficients were -0.87 and -0.61 (p < 0.001), respectively. Furthermore, there was a positive correlation between cancer stemness index and cell purity (p < 0.001). The cancer stemness index in the metastasis group was higher than that in the non-metastasis group (p = 0.0017). After adjusting for tumor purity, there was no significant correlation between T-cell infiltration and cancer stemness index (p = 0.086). Through the pharmacological mechanism of topoisomerase inhibitors, six molecular complexes may be the targets of GIST treatment. Conclusion: Immune infiltration in GIST patients is related to cancer stem-like properties, and the correlation relies on tumor purity. Cancer stemness index can be used as a new predictive biomarker of tumor metastasis and targets of drug therapy for GIST patients.

3.
J Gastrointest Oncol ; 12(5): 2022-2034, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34790370

RESUMO

Background: The aim of our study was to examine the impact of the combination of the ratio between metastatic and harvested lymph nodes (RML) and negative lymph node (NLN) count on overall survival (OS) in patients with advanced gastric cancer (GC). Methods: The clinicopathological data of 2,952 advanced GC patients who received curative resection between 1994 and 2015 were collected. They were divided into four groups according to the RML: 0, 0-0.1, 0.1-0.4, and >0.4. We distinguished survival differences through Kaplan-Meier analysis among the subgroups to investigate the impacts of the RML on OS in advanced GC patients. OS was examined according to clinicopathological variables. Spearman's correlation coefficient was used to assess the relationships between the RML and metastatic lymph node (MLN) count and NLN count. Results: A total of 1,182 patients were enrolled into the study. The median follow-up time was 39 months (interquartile range 20 to 68 months). The 5-year OS rate of all 1,182 GC patients was 54.4%. Kaplan-Meier survival analysis showed that the median OS declined significantly with increasing RML (5-year survival rate 81.2% vs. 69.1% vs. 42.8% vs. 13.1%, P<0.001). As the NLN count increased, the survival rate of GC patients increased (5-year survival rate 12.8% vs. 25.2% vs. 60.2%, P<0.05). The RML, not NLN count, was identified as an independent factor for OS (P<0.001) through multivariate analysis. Spearman correlation analysis suggested that the RML was positively correlated with the number of MLNs (ρ=0.973, P<0.001) and inversely associated with the NLN count (ρ=-0.513, P<0.001). Conclusions: The RML is an independent prognostic predictor of OS in advanced GC patients, and the NLN count may serve as a supplementary strategy for the present tumor-node-metastasis (TNM) classification to further improve the prognostic prediction efficiency. The combination of the RML and NLN count should be an important predictor for current clinical applications.

4.
BMC Cancer ; 21(1): 1084, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620113

RESUMO

BACKGROUND & AIMS: Little is known on the gender-specific effect and potential role of non-linear associations between metabolic syndrome (MetS) components and liver cancer risk. We evaluated these associations based on the UK Biobank cohort. METHODS: We included 474,929 individuals without previous cancer based on the UK Biobank cohort. Gender-specific hazard ratios (HRs) and 95% confidence interval (CIs) were calculated by Cox proportional hazards regression, adjusting for potential confounders. Non-linear associations for individual MetS components were assessed by the restricted cubic spline method. RESULTS: Over a median follow-up of 6.6 years, we observed 276 cases of liver cancer (175 men, 101 women). MetS [HR 1.48, 95% CI 1.27-1.72] and central obesity [HR 1.65, 95% CI 1.18-2.31] were associated with higher risk of liver cancer in men but not in women. Participants with hyperglycaemia has higher risk of liver cancer. High waist circumference and blood glucose were dose-dependently associated with increased liver cancer risk in both genders. For high density lipoprotein (HDL) cholesterol (both genders) and blood pressure (women), U-shaped associations were observed. Low HDL cholesterol (< 1.35 mmol/L) in men and high HDL cholesterol in women (> 1.52 mmol/L) were associated with increased liver cancer risk. CONCLUSIONS: MetS components showed gender-specific linear or U- shaped associations with the risk of liver cancer. Our study might provide evidence for individualized management of MetS for preventing liver cancer.


Assuntos
Neoplasias Hepáticas/etiologia , Síndrome Metabólica/complicações , Fatores Sexuais , Adulto , Idoso , Glicemia , HDL-Colesterol/sangue , Intervalos de Confiança , Feminino , Seguimentos , Humanos , Hiperglicemia/complicações , Hipertensão/complicações , Hipertrigliceridemia/complicações , Neoplasias Hepáticas/epidemiologia , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Obesidade Abdominal/complicações , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologia , Circunferência da Cintura
5.
Front Cell Dev Biol ; 9: 726716, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621744

RESUMO

Background: Gastric cancer (GC) remains one of the most malignant tumors around the world, and an accurate model that reliably predicts survival and therapeutic efficacy is urgently needed. As a novel predictor for prognosis in a variety of cancers, immune-related long noncoding RNA pairs (IRlncRNAPs) have been reported to predict tumor prognosis. Herein, we integrated an IRlncRNAPs model to predict the clinical outcome, immune features, and chemotherapeutic efficacy of GC. Methods: Based on the GC data obtained from The Cancer Genome Atlas (TCGA) database and the Immunology Database and Analysis Portal (ImmPort), differentially expressed immune-related long noncoding RNAs (DEIRlncRNAs) were identified. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression analysis were used to select the most appropriate overall survival (OS)-related IRlncRNAPs to develop a prognostic signature. The riskScore of each sample was calculated by comparing the long noncoding RNA expression level in each IRlncRNAP. Based on the riskScore for each patient, GC patients were divided into high- and low-risk groups. Then, the correlation of the signature and riskScore with OS, clinical features, immune cell infiltration, immune-related gene (IRG) expression and chemotherapeutic efficacy in GC was analyzed. Results: A total of 107 DEIRlncRNAs were identified which formed 4297 IRlncRNAPs. Fifteen OS-related IRlncRNAPs were selected to develop a prognostic model. GC patients could be accurately classified into high- and low-risk groups according to the riskScore of the prognostic model. The 1-, 2-, 3-, and 5-year receiver operating characteristic (ROC) curves for the riskScore were drawn and the area under the curve (AUC) values were found to be 0.788, 0.810, 0.825, and 0.868, respectively, demonstrating a high sensitivity and accuracy of this prognostic signature. Moreover, the immune-related riskScore was an independent risk factor. Patients showed a poorer outcome within the high-risk group. In addition, the riskScore was found to be significantly correlated with the clinical features, immune infiltration status, IRG expression, and chemotherapeutic efficacy in GC. Conclusion: The prognostic model of IRlncRNAPs offers great promise in predicting the prognosis, immune infiltration status, and chemotherapeutic efficacy in GC, which might be helpful for the selection of chemo- and immuno-therapy of GC.

6.
Front Cell Dev Biol ; 9: 716461, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660578

RESUMO

Background: Focal adhesion, as the intermediary between tumor cells and extracellular matrix communication, plays a variety of roles in tumor invasion, migration, and drug resistance. However, the potential role of focal adhesion-related genes in the microenvironment, immune cell infiltration, and drug sensitivity of gastric cancer (GC) has not yet been revealed. Methods: The genetic and transcriptional perspectives of focal adhesion-related genes were systematically analyzed. From a genetic perspective, the focal adhesion index (FAI) was constructed based on 18 prognosis-related focus adhesion-related genes to evaluate the immune microenvironment and drug sensitivity. Then three prognosis-related genes were used for consistent clustering to identify GC subtypes. Finally, use FLT1, EGF, COL5A2, and M2 macrophages to develop risk signatures, and establish a nomogram together with clinicopathological characteristics. Results: Mutations in the focal adhesion-related gene affect the survival time and clinical characteristics of GC patients. FAI has been associated with a shorter survival time, immune signaling pathways, M2 macrophage infiltration, epithelial-mesenchymal transition (EMT) signaling, and diffuse type of GC. FAI recognizes ALK, cell cycle, and BMX signaling pathways inhibitors as sensitive agents for the treatment of GC. FLT1, EGF, and COL5A2 may distinguish GC subtypes. The established risk signature is of great significance to the prognostic evaluation of GC based on FLT1, EGF, and COL5A2 and M2 macrophage expression. Conclusion: The focal adhesion-related gene is a potential biomarker for the evaluation of the immune microenvironment and prognosis. This work emphasizes the potential impact of the focal adhesion pathway in GC therapy and highlights its guiding role in prognostic evaluation.

7.
Autophagy ; : 1-16, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34632918

RESUMO

Macrophages rapidly undergo glycolytic reprogramming in response to macroautophagy/autophagy, inflammasome activation and pyroptosis for the clearance of bacteria. Identification the key molecules involved in these three events will provide critical potential therapeutic applications. Upon S. typhimurium infection, FLT4/VEGFR3 and its ligand VEGFC were inducibly expressed in macrophages, and FLT4 signaling inhibited CASP1 (caspase 1)-dependent inflammasome activation and pyroptosis but enhanced MAP1LC3/LC3 activation for elimination of the bacteria. Consistently, FLT4 mutants lacking the extracellular ligand-binding domain increased production of the proinflammatory metabolites such as succinate and lactate, and reduced antimicrobial metabolites including citrate and NAD(P)H in macrophages and liver upon infection. Mechanistically, FLT4 recruited AMP-activated protein kinase (AMPK) and phosphorylated Y247 and Y441/442 in the PRKAA/alpha subunit for AMPK activation. The AMPK agonist AICAR could rescue glycolytic reprogramming and inflammasome activation in macrophages expressing the mutant FLT4, which has potential translational application in patients carrying Flt4 mutations to prevent recurrent infections. Collectively, we have elucidated that the FLT4-AMPK module in macrophages coordinates glycolytic reprogramming, autophagy, inflammasome activation and pyroptosis to eliminate invading bacteria.

8.
Front Cell Dev Biol ; 9: 719192, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497808

RESUMO

Oxaliplatin (OXA) resistance in the treatment of different types of cancer is an important and complex problem. The culture of tumor organoids derived from gastric cancer can help us to provide a deeper understanding of the underlying mechanisms that lead to OXA resistance. In this study, our purpose was to understand the mechanisms that lead to OXA resistance, and to provide survival benefits to patients with OXA through targeted combination therapies. Using sequence analysis of OXA-resistant and non-OXA-resistant organoids, we found that PARP1 is an important gene that mediates OXA resistance. Through the patients' follow-up data, it was observed that the expression level of PARP1 was significantly correlated with OXA resistance. This was confirmed by genetic manipulation of PARP1 expression in OXA-resistant organoids used in subcutaneous tumor formation. Results further showed that PARP1 mediated OXA resistance by inhibiting the base excision repair pathway. OXA also inhibited homologous recombination by CDK1 activity and importantly made cancers with normal BRCA1 function sensitive to PARP inhibition. As a result, combination of OXA and Olaparib (PARP-1/2/3 inhibitor), inhibited in vivo and in vitro OXA resistant organoid growth and viability.

9.
J Tissue Eng Regen Med ; 15(11): 1012-1022, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34555270

RESUMO

Organoid culture is a recently developed in vitro three-dimensional (3D) cell culture technology. It has wide applications in tissue engineering studies. However, histological analysis of organoid is quite complex and tedious for researchers. This study proposes a user-friendly, affordable and efficient method for making formalin-fixed paraffin embedded (FFPE) organoid blocks and Optimal Cutting Temperature compound (OCT) embedded frozen organoid blocks. This method implements a key pre-embedding step for preparing paraffin embedded organoid blocks, which could concentrate organoid together without damaging or loss of samples. This method could be used to process even a small number of organoids with high efficiency. In addition, with minor modifications, the method is readily applied for OCT embedded organoid blocks. The slides generated were ready for H&E staining, immunohistochemistry staining and immunofluorescent staining. The method described in this study can be easily used for routine histological analysis of organoid, and could be performed in general pathology labs and requires no dedicated equipment and reagent.

10.
Cell Mol Gastroenterol Hepatol ; 13(1): 95-112, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34537439

RESUMO

BACKGROUND & AIMS: Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. APPROACH & RESULTS: Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K-/- mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K-/- mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA-based silencing of p70S6K in HSC lines, experiments with p70S6K-/- cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K-/- mice developed significantly less fibrosis upon exposure to CCl4. CONCLUSIONS: We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment.

11.
Front Oncol ; 11: 668707, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485116

RESUMO

Immunosuppressive molecules are valuable prognostic biomarkers across different cancer types. Leukocyte immunoglobulin like receptor subfamily B1 (LILRB1) is considered to be an immunosuppressive molecule, which is an important receptor of human leukocyte antigen G. However, the clinical significance of LILRB1 expression in gastric cancer remains unexplored. We analyzed the immunohistochemistry data of 166 gastric cancer patients to determine the clinicopathologic and survival significance of LILRB1. Immunofluorescence was conducted to detect the co-localization of LILRB1 with infiltrating immune cells. Additionally, we also assessed the immune contexture, immune cell functions and tumor microenvironment state related to LILRB1. We found that LILRB1 was mainly present in tumor stroma which was higher in tumor tissues compared with matched adjacent tissues. High-LILRB1 expression was associated with more advanced tumor stage, higher recurrence risk and worse survival. Immunohistochemistry and bioinformatic analysis showed that LILRB1 had a significant positive correlation with M2 tumor-associated macrophages (TAMs) infiltration. Immunofluorescence confirmed that M2 TAMs were the primary immune cells expressing LILRB1. Dense infiltration of LILRB1+ M2 TAMs yielded an immunosuppressive microenvironment manifested as enriched exhausted CD8+ T cells and increased immunosuppressive cytokines. Moreover, patients with high infiltration of both LILRB1+ cells and M2 TAMs indicated poor prognosis and inferior therapeutic responsiveness to adjuvant chemotherapy. In conclusion, LILRB1+ M2 TAMs were associated with a pro-tumor immune contexture and determine poor prognosis in gastric cancer. Further studies are essential to explore therapeutic targeting LILRB1+ M2 TAMs.

12.
Gland Surg ; 10(8): 2591-2599, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34527570

RESUMO

Background: Standardized and transparent reporting of surgical technique is the cornerstone of effective dissemination, implementation and improvement. However, current reporting of surgical techniques is inadequate. The existing guidelines potentially applied to guide surgical technique reporting are with a minimal highlight of the surgical technique, lack requirements explaining what extent and dimensions need to be described in detail, or are unlikely to extrapolate to a wide range of surgical techniques. This study aims to formulate a rigorous protocol to develop a surgical technique reporting checklist and standards (SUPER) that defines what a clear, comprehensive and detailed surgical technique report should be contained. Methods: This protocol is designed following the classic guidance for developing reporting guidelines recommended by the EQUATOR network. Results: The development team will consist of surgeons (~80%), methodologists, and journal editors. The draft checklist sources will include a scoping review of existing reporting guidelines related to surgical technique, surgical technique articles from 15 top journals published in the last year, and brainstorming by the multidisciplinary development team. The final SUPER checklist will be formed after three rounds of Delphi surveys, one round of face-to-face meeting, and a month-long pilot test. The SUPER checklist will be published as open-access and be used in combination with existing reporting guidelines related to surgical techniques (e.g., IDEAL). This protocol will steer the SUPER checklist's development, allowing us to further elaborate surgical technique reporting for all surgical specialties, and enabling a more favorable experience for surgeons, nurses, medical students, residents, editors, and reviewers. Trial Registration: This trial is registered at the EQUATOR network on December 18th, 2020. Available at: https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-other-study-designs/.

13.
Gastroenterology ; 161(6): 1842-1852.e10, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34389338

RESUMO

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) have a major impact on gut microbiome and immune function, which in turn, may increase the risk of inflammatory bowel disease (IBD). Our aim in this study was to evaluate PPI use and subsequent risk of IBD and subtypes (ie, Crohn's disease and ulcerative colitis). METHODS: This was a pooled analysis of the Nurses' Health Study (NHS, n = 82,869), NHS II (n = 95,141), and UK Biobank (n = 469,397). We included participants with information on personal use of PPIs and free of IBD or cancer at baseline. We evaluated hazard ratios and 95% confidence intervals (CIs) with Cox regression adjusting for lifestyle factors, PPI indications, comorbidities, and other medications. RESULTS: We documented 271 cases of IBD (median follow-up, 12 years) in the pooled NHS cohorts and 1419 cases (median follow-up, 8.1 years) in the UK Biobank. For both pooled NHS cohorts and UK Biobank, regular use of PPIs consistently showed a significantly positive association with IBD, Crohn's disease, and ulcerative colitis risk. Combined analyses of 3 cohorts showed that regular PPI users had an increased risk of IBD as compared with nonusers (hazard ratio, 1.42; 95% CI, 1.22-1.65; number needed to harm, 3770; 95% CI, 3668-4369). Direct comparison with H2 receptor antagonist, a less potent acid suppressor, showed that PPI use was also associated with higher IBD risk (hazard ratio, 1.38; 95% CI, 1.16-1.65). CONCLUSIONS: Regular use of PPIs was associated with an increased risk of IBD and its subtypes. The findings should be interpreted with caution because the absolute risk was low and the clinical benefits of PPIs are substantial.

14.
Int J Biol Sci ; 17(11): 2811-2825, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34345209

RESUMO

Chemotherapy plays an irreplaceable role in the treatment of GC, but currently available chemotherapeutic drugs are not ideal. The application of medicinal plants is an important direction for new drug discovery. Through drug screening of GC organoids, we determined that ailanthone has an anticancer effect on GC cells in vitro and in vivo. We also found that AIL can induce DNA damage and apoptosis in GC cells. Further transcriptome sequencing of PDX tissue indicated that AIL inhibited the expression of XRCC1, which plays an important role in DNA damage repair, and the results were also confirmed by western blotting. In addition, we found that AIL inhibited the expression of P23 and that inhibition of P23 decreased the expression of XRCC1, indicating that AIL can regulate XRCC1 via P23. The results of coimmunoprecipitation showed that AIL can inhibit the binding of P23 and XRCC1 to HSP90. These findings indicate that AIL can induce DNA damage and apoptosis in GC cells. Meanwhile, AIL can decrease XRCC1 activity by downregulating P23 expression to inhibit DNA damage repair. The present study sheds light on the potential application of new drugs isolated from natural medicinal plants for GC therapy.

15.
PeerJ ; 9: e12000, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34458026

RESUMO

Effector proteins translocated by the Dot/Icm type IV secretion system determine the virulence of Legionella pneumophila (L. pneumophila). Among these effectors, members of the SidE family (SidEs) regulate several cellular processes through a unique phosphoribosyl ubiquitination mechanism mediated by another effector, SidJ. Host-cell calmodulin (CaM) activates SidJ to glutamylate the SidEs of ubiquitin (Ub) ligases and to make a balanced Ub ligase activity. Given the central role of SidJ in this regulatory process, studying the nature of evolution of sidJ is important to understand the virulence of L. pneumophila and the interaction between the bacteria and its hosts. By studying sidJ from a large number of L. pneumophila strains and using various molecular evolution algorithms, we demonstrated that intragenic recombination drove the evolution of sidJ and contributed to sidJ diversification. Additionally, we showed that four codons of sidJ which are located in the N-terminal (NTD) (codons 58 and 200) and C-terminal (CTD) (codons 868 and 869) domains, but not in the kinase domain (KD) had been subjected to strong positive selection pressure, and variable mutation profiles of these codons were identified. Protein structural modeling of SidJ provided possible explanations for these mutations. Codons 868 and 869 mutations might engage in regulating the interactions of SidJ with CaM through hydrogen bonds and affect the CaM docking to SidJ. Mutation in codon 58 of SidJ might affect the distribution of main-chain atoms that are associated with the interaction with CaM. In contrast, mutations in codon 200 might influence the α-helix stability in the NTD. These mutations might be important to balance Ub ligase activity for different L. pneumophila hosts. This study first reported that intragenic recombination and positive Darwinian selection both shaped the genetic plasticity of sidJ, contributing to a deeper understanding of the adaptive mechanisms of this intracellular bacterium to different hosts.

16.
Bio Protoc ; 11(15): e4117, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34458411

RESUMO

Characterization of key regulators in vein development will advance our understanding of mechanisms underlying venous anomalies and provide therapeutic targets for the treatment of vascular malformations. Here, we provide a detailed protocol for the generation of genetically engineered mouse models targeting the Tek gene for the analysis of vein formation and vein-associated vascular diseases at the embryonic and postnatal stages. It includes steps involved in the whole-mount processing of mouse skin, mesentery, and retina for the examination of vascular malformation during embryonic and postnatal development.

17.
J Exp Clin Cancer Res ; 40(1): 260, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412665

RESUMO

BACKGROUND: Oxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro. METHODS: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect. RESULTS: We found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis. CONCLUSIONS: This study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy.

18.
Ann Transl Med ; 9(13): 1046, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34422958

RESUMO

Background: The influence of pretreatment anemia on the prognosis of patients with advanced gastric cancer (GC) remains controversial. We retrospectively examined the impact of pretreatment anemia on the overall survival (OS) of patients with GC with nonhypoalbuminemia undergoing curative resection. Methods: The clinicopathological data of 2,916 patients with advanced GC who received a radical gastrectomy from 1994 to 2015 were analyzed. The patients were divided into two subgroups by hemoglobin level, <120 and ≥120 g/L. OS was analyzed using the Kaplan-Meier method, and a multivariate Cox proportional hazards model was used to identify the independent prognostic factor. Results: A total of 1,099 patients were included in our study. The median follow-up duration was 43 (IQR, 24-66) months. The prevalence of anemia was 40.9%. Among these 1,099 patients, 505 (46.0%) had nonhypoalbuminemia. Kaplan-Meier survival analysis showed that patients with GC who were anemic had a poorer OS than patients who were not (5-year OS rate: 58.4% vs. 66.8%, P<0.0001). Multivariate analysis revealed that pretreatment anemia was an independent prognostic factor [hazard ratio (HR) =1.455, 95% CI, 1.013-2.09; P=0.043]. Conclusions: Our findings indicate that pretreatment anemia may serve as an independent prognostic factor for patients with advanced GC with nonhypoalbuminemia after radical gastrectomy, especially those with larger tumor size and pT3 disease.

19.
Eur J Med Chem ; 224: 113720, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34332399

RESUMO

Fatty acid-binding protein 4 (FABP4) and fatty acid-binding protein 5 (FABP5) are promising therapeutic targets for the treatment of various metabolic diseases. However, the weak potency, low selectivity over FABP3, or poor pharmacokinetic profiles of currently reported dual FABP4/5 inhibitors impeded further research. Here, we described the characterization of a series of dual FABP4/5 inhibitors with improved metabolic stabilities and physicochemical properties based on our previous studies. Among the compounds, D9 and E1 exhibited good inhibitory activities against FABP4/5 and favorable selectivity over FABP3 in vitro. In cell-based assays, D9 and E1 exerted a decrease of FABP4 secretion, a strong anti-lipolytic effect in mature adipocytes, and suppression of MCP-1 expression in THP-1 macrophages. Moreover, D9 and E1 possessed good metabolic stabilities in mouse hepatic microsomes and acceptable pharmacokinetics profiles in ICR mice. Further in vivo experiments showed that D9 and E1 could potently decrease serum FABP4 levels and ameliorate glucose metabolism disorders in obese diabetic db/db mice. These results demonstrated that D9 and E1 could serve as lead compounds for the development of novel anti-diabetic drugs.

20.
Am J Gastroenterol ; 116(11): 2286-2291, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34313608

RESUMO

INTRODUCTION: The association between proton pump inhibitors' (PPIs) use and mortality remains unclear. METHODS: This was a prospective analysis of 440,840 UK residents and 13,154 deaths. We evaluated the associations with multivariate Cox regression. RESULTS: After adjusting for confounders, such as over health status and longstanding diseases, the regular use of PPIs was not associated with an increased risk of all-cause mortality and mortality due to neoplasms, circulatory system diseases, respiratory system diseases, digestive system diseases, external causes, and other causes. DISCUSSION: Regular use of PPIs was not associated with an increased risk of all-cause and cause-specific mortality.


Assuntos
Causas de Morte , Inibidores da Bomba de Prótons/efeitos adversos , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...